Primary liver cancer is one of the most common types of cancer in the world, with several hundred thousand new cases diagnosed annually. Of these, approximately 80% to 90% are hepatocellular carcinoma (HCC), also known as hepatoma. HCC is most prevalent in Asia and sub-Saharan Africa; in China alone there are more than 450,000 new cases per year, representing the fourth leading cause of death overall. HCC is the fastest increasing type of cancer in the United States: approximately 19,000 new cases are diagnosed annually, with resulting mortality of more than 16,000 per year.
Liver cancer commonly develops from liver cirrhosis, particularly that caused by hepatitis B or hepatitis C. The high incidence of liver cirrhosis and liver cancer found in Asia and Africa is due in large part to the high prevalence of hepatitis B and, increasingly, hepatitis C throughout these regions. The rising incidence of hepatitis C throughout the world is leading to an increase of liver cancer in other regions as well.
Cirrhosis due to causes other than hepatitis, including ingestion of ethanol and exposure to other organic solvents, can also lead to liver cancer. In addition, the ingestion of certain aflatoxins, which are toxins than can occur in stored grains and other foods as the result of fungal growth, is also associated with the development of liver cancer, as is the ingestion of other food- and water-borne carcinogens, including many drugs. Liver cancer may also arise from exposure to radiation, from mechanical trauma, and from other causes.
The current treatment of liver cancer is primarily surgical. If the cancer is localized to a particular region of the liver, and if that region can be safely removed, then surgical treatment may be successful. For the great majority of liver cancer patients, however, by the time the liver cancer is detected, too much of the liver is affected for surgical treatment to be safe and effective, and the cancer has commonly metastasized beyond the liver. Currently, these patients have few, if any, treatment options.
Gallium has repeatedly shown efficacy in treating certain cancers (Bernstein L R, PHARMACOL REV 50:665-682, 1998). In particular, gallium is known to be effective in treating lymphoma, multiple myeloma, prostate cancer, and bladder cancer. Topically or transdermally administered gallium is effective in treating hyperproliferative skin disorders such as psoriasis and skin cancer, and related dermatologic disorders (U.S. Pat. No. 5,747,482 to Bernstein). Gallium compounds, including gallium nitrate and gallium maltolate, also have anti-inflammatory activity; particular efficacy for gallium has been reported in animal models for inflammatory autoimmune diseases, such as rheumatoid arthritis (Delbarre F, Rabaud M, COMPTES RENDUS DE L'ACADÉMIE DES SCIENCES, Series D 283:1469-1472, 1976; Matkovic V et al., CURRENT THERAPEUTIC RESEARCH 50:255-267, 1991; U.S. Pat. No. 5,175,006), multiple sclerosis (Whitacre C et al., JOURNAL OF NEUROIMMUNOLOGY 39:175-182, 1992), uveitis (Lobanoff M C et al., EXPERIMENTAL EYE RESEARCH 65:797-801, 1997), and Type 1 diabetes (Flynn J O et al., DIABETES 41:38A, 1992). Gallium is also effective at inhibiting the loss of calcium from bone resulting from cancer, Paget's disease of bone, and other causes, and can be used to treat hypercalcemia associated with cancer. It is also known that gallium radioisotopes, such as 67Ga, concentrate in many types of neoplastic tissue, including liver cancer. Despite the use of gallium to treat and diagnose certain cancers and other diseases since the early 1970s, there has never been any suggestion to use gallium in the treatment of liver cancer or related disorders. It has now been found that gallium appears particularly effective at treating and preventing liver cancer.